Molecular and cellular exercise physiology

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Group members in the research group Molecular and cellular exercise physiology

Sedentary lifestyles seem to come at a high cost to our health and have been linked to the incidence of several diseases including diabetes, obesity, cardiovascular disease, neurodegenerative diseases (such as Alzheimer’s and Parkinson’s), mood disorders (e.g. depression), and even cancer. Physical activity and skeletal muscle condition play a clear role in the prevention and treatment of these diseases. However, exercise programs are not always viable treatment options due to inherent disease characteristics such as muscle weakness, difficulty in movement, or, in particular, patient compliance.

By studying the mechanisms by which skeletal muscle adapts to different challenges and positively affects so many aspects of human health, we can learn valuable lessons that can be translated into future disease therapies. 

Illustration of muscles and organs in the human body

Research in our laboratory

Research in our laboratory is aimed at understanding the molecular mechanisms that mediate skeletal muscle adaptations to diverse challenges and their local and systemic consequences. We are particularly interested in understanding how exercised or sedentary skeletal muscle can crosstalk with other organs, and how it can affect individual health and disease.

Video and audio about our research

How physical exercise protects the brain from stress-induced depression - Lecture by Jorge Ruas at the Steno Diabetes Center, November 2014

 

Listen to a recorded seminar about the research in our group: EASD virtual meeting: Jorge Ruas on "Exercise impact on muscle mass and function - role of PGC-1 alpha"

Press releases

How physical exercise protects the brain from stress-induced depression. Press release from Karolinska Institutet September 26, 2014

Novel protein makes muscles bigger and stronger. Press release from Karolinska Institutet February 7, 2012

Group members

Jorge Ruas Associate Professor, Research group leader
Leandro Agudelo Doctoral student 
Igor Cervenka Postdoc 
Jorge Correia Postdoc
Duarte Ferreira Postdoc 
Manizheh Izadi Doctoral student
Lars Ketscher Postdoc
Amanda Klein Postdoc
Vicente Martinez-Redondo Postdoc

Margareta Porsmyr-Palmertz

Research technician, Biomedical scientist
Paula da Silva Doctoral student

Rotations and internships

Paulo Jannig (2016). Visiting PhD student. From the University Sao Paulo (Brazil).

Miguel Moutinho (2016). Visiting PhD student. From the University of Lisbon (Portugal).

Abdirahman Farah (2015). Internship. From the Biomedicine Masters program at Karolinska Institutet (Stockholm, Sweden).

Shamim Dadvar (2015). Internship. From the Medicine undergraduate program at Karolinska Institutet (Stockholm, Sweden).

Alicia Hansson (2015). Degree Project. From the Medicine undergraduate program at Karolinska Institutet (Stockholm, Sweden). (In collaboration with Dr. Sreekumaran Nair at the Mayo Clinic, USA).

Austin Lee (2014). Internship. From the Life Science undergraduate program at Harvard College (Boston MA, USA).

Fredrik Wernstål (2014). Internship. From the Medicine undergraduate program at Karolinska Institutet (Stockholm, Sweden).

Charles Petipré (2014). Master’s thesis. MSc in Genomics and Proteomics. Université de Lille. (Lille, France). Supported by the Erasmus Programme.

Benedicta Ugochi Iwuagwu (2013). Internship. MSc in Biomedicine, Karolinska Institutet (Stockholm, Sweden). Recipient of Karolinska Institutet's Global scholarship award, 2011.

Oscar Andén (2013/2014). Internship. From the Biomedicine undergraduate program, Karolinska Institutet. 

Vera Blaschke. (2013/2014). Internship. Bachelor’s degree in Life Science. University of Konstanz (Germany). Recipient of a Leonardo da Vinci programme scholarship (European Commission).

Projects

The common goal of the projects being developed in our laboratory is to better understand the signal transduction and gene regulatory pathways that control skeletal muscle function in health and disease. With this knowledge, we aim at developing strategies that can be used as possible therapeutic avenues for the treatment of metabolic and degenerative diseases.

Current projects

Mechanisms of regulation of skeletal muscle size and strength

Skeletal muscle is an extremely plastic tissue that can use energy to generate work, generate energy by breaking down proteins into amino acids, undergo atrophy, hypertrophy, and even change its metabolism when stimulated by distinct exercise programs (that is, endurance versus resistance training). By using a combination of genomics and proteomics approaches with different genetic models of skeletal muscle conditioning we hope to uncover new pathways important for the regulation of skeletal muscle mass and function.

Skeletal muscle metabolism and its crosstalk to the central nervous system

The beneficial effects of physical exercise on the prevention and treatment of neurodegenerative and mood diseases are well known. However, the mechanisms that mediate these effects are not completely understood. We have recently shown that skeletal muscle metabolism of the tryptophan metabolite kynurenine can protect form stress-induced depression by preventing the neuroinflammation associated with brain accumulation of this molecule. Our lab continues invested in trying to better understand how information is conveyed between peripheral tissues and to the brain. 

A bioengineering approach to study inter-organ communication

Although it is clear that during skeletal muscle adaptation to diverse stimuli, including physical exercise, information is exchanged between this and other tissues in the body, the mechanisms that mediate this communication remain in great part elusive. Additionally, there are inherent difficulties in establishing causality in in vivo systems and the search for circulating secreted factors is hindered by the challenge of unbiased screening in the complex blood compartment. We are using mini-tissue microfluidics systems to model the information flow between skeletal muscle and other tissues. Tissue-specific functions are monitored by sensors including temperature probes and contractility measurements. The defined nature of these systems will facilitate the identification and manipulation of circulating factors affecting tissue function and metabolism. 

Modulation of PGC-1alpha1 activity in skeletal muscle

Skeletal muscle adaptation to exercise training is mediated by the concerted actions of several transcriptional regulators, among which PGC-1alpha proteins play a central role. PGC-1alpha1 belongs to a family of coactivator proteins (together with PGC-1beta and PRC) and is highly induced in tissues with high energy demands by signals that increase energy output, such as cold and exercise. When activated, PGC-1alpha1 induces genes relevant to mitochondrial biogenesis, adaptive thermogenesis, lipid and glucose homeostasis, fiber-type switching, among other processes. For these reasons, deficiencies in PGC-1alpha1 activity have been suggested to be involved in pathogenic conditions such as obesity, diabetes, sarcopenia, and neurodegeneration. Conversely, it has been shown that overexpression of PGC-1alpha1 in murine skeletal muscle has several beneficial effects. We are developing strategies to increase PGC-1alpha1 levels in muscle, which small molecule technologies. The efficiency of these strategies is being tested in vitro and in vivo in the context of metabolic and muscular diseases.

PGC-1alpha splice isoform function in skeletal muscle

We have identified several new PGC-1alpha variants that are expressed at significant levels in skeletal muscle and several other tissues. Transcription of these isoforms is initiated at an alternative promoter of the PGC-1alpha gene, which seems to also induce alternative mRNA splicing. Among these, the PGC-1alpha4 variant is induced by resistance exercise training and specifically promotes skeletal muscle growth and strength. Importantly, transgenic animals with elevated PGC-1alpha4 levels in skeletal muscle show increased exercise performance, and resistance to atrophy and to cancer-induced cachexia. The functions of PGC-1alpha2 and 3 remain unknown. We are exploring the biological functions of these proteins using a combination of biochemical and genetic approaches.

Financial support

Current

Previous

Recent publications

Neuronal cholesterol metabolism increases dendritic outgrowth and synaptic markers via a concerted action of GGTase-I and Trk.
Moutinho M, Nunes M, Correia J, Gama M, Castro-Caldas M, Cedazo-Minguez A, et al
Sci Rep 2016 ;6():30928

 

The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction.
Salah H, Li M, Cacciani N, Gastaldello S, Ogilvie H, Akkad H, et al
Sci Transl Med 2016 Aug;8(350):350ra103

 

Targeting mitochondrial mRNA translation to tackle obesity-induced insulin resistance: thumbs up for exercise.
Jannig P, Ruas J
Acta Physiol (Oxf) 2016 Jul;():

 

Peroxisome Proliferator-activated Receptor γ Coactivator-1 α Isoforms Selectively Regulate Multiple Splicing Events on Target Genes.
Martínez-Redondo V, Jannig P, Correia J, Ferreira D, Cervenka I, Lindvall J, et al
J. Biol. Chem. 2016 Jul;291(29):15169-84

 

Endurance exercise increases skeletal muscle kynurenine aminotransferases and plasma kynurenic acid in humans.
Schlittler M, Goiny M, Agudelo L, Venckunas T, Brazaitis M, Skurvydas A, et al
Am. J. Physiol., Cell Physiol. 2016 May;310(10):C836-40

 

Mechano-signalling pathways in an experimental intensive critical illness myopathy model.
Corpeno Kalamgi R, Salah H, Gastaldello S, Martinez-Redondo V, Ruas J, Fury W, et al
J. Physiol. (Lond.) 2016 Aug;594(15):4371-88

 

Inflammation, immunology, stress and depression: a role for kynurenine metabolism in physical exercise and skeletal muscle.
Zepf F, Stewart R, Guillemin G, Ruas J
Acta Neuropsychiatr 2016 Aug;28(4):244-5

 

Bioenergetic cues shift FXR splicing towards FXRα2 to modulate hepatic lipolysis and fatty acid metabolism.
Correia J, Massart J, de Boer J, Porsmyr-Palmertz M, Martínez-Redondo V, Agudelo L, et al
Mol Metab 2015 Dec;4(12):891-902

 

Ryanodine receptor fragmentation and sarcoplasmic reticulum Ca2+ leak after one session of high-intensity interval exercise.
Place N, Ivarsson N, Venckunas T, Neyroud D, Brazaitis M, Cheng A, et al
Proc. Natl. Acad. Sci. U.S.A. 2015 Dec;112(50):15492-7

 

The hitchhiker's guide to PGC-1α isoform structure and biological functions.
Martínez-Redondo V, Pettersson A, Ruas J
Diabetologia 2015 Sep;58(9):1969-77

 

Intercellular: local and systemic actions of skeletal muscle PGC-1s.
Correia J, Ferreira D, Ruas J
Trends Endocrinol. Metab. 2015 Jun;26(6):305-14

 

Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression.
Agudelo L, Femenía T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, et al
Cell 2014 Sep;159(1):33-45

 

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Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis.
Rao R, Long J, White J, Svensson K, Lou J, Lokurkar I, et al
Cell 2014 Jun;157(6):1279-91

 

Loss of Pgc-1α expression in aging mouse muscle potentiates glucose intolerance and systemic inflammation.
Sczelecki S, Besse-Patin A, Abboud A, Kleiner S, Laznik-Bogoslavski D, Wrann C, et al
Am. J. Physiol. Endocrinol. Metab. 2014 Jan;306(2):E157-67

 

A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy.
Ruas J, White J, Rao R, Kleiner S, Brannan K, Harrison B, et al
Cell 2012 Dec;151(6):1319-31

 

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Separation of the gluconeogenic and mitochondrial functions of PGC-1{alpha} through S6 kinase.
Lustig Y, Ruas J, Estall J, Lo J, Devarakonda S, Laznik D, et al
Genes Dev. 2011 Jun;25(12):1232-44

 

The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex.
Wu J, Ruas J, Estall J, Rasbach K, Choi J, Ye L, et al
Cell Metab. 2011 Feb;13(2):160-9

 

PGC-1alpha regulates a HIF2alpha-dependent switch in skeletal muscle fiber types.
Rasbach K, Gupta R, Ruas J, Wu J, Naseri E, Estall J, et al
Proc. Natl. Acad. Sci. U.S.A. 2010 Dec;107(50):21866-71

 

Retrograde influence of muscle fibers on their innervation revealed by a novel marker for slow motoneurons.
Chakkalakal J, Nishimune H, Ruas J, Spiegelman B, Sanes J
Development 2010 Oct;137(20):3489-99

 

 

Seminars hosted by our lab

November 2015 - Eleftheria-Maratos Flier

Visiting researcher: Terry Flier, M.D. Professor of Medicine at the Beth-Israel Deaconess Mecial Centre (BIDMC) and Harvard Medical School, Boston, USA.
Title of seminar: Pleiotropic actions of FGF21 serve to integrate metabolism

Poster: seminar by Eleftheria-Maratos Flier at KI November 2015

September 2014 - Patrick Seale

Visiting researcher: Patrick Seale, Ph.D., Assistant Professor of Cell and Developmental Biology at the Perelman School of Medicine, University of Pennsylvania.
Title of seminar: Transcriptional control of brown and beige fat cell identity.

Poster: seminar by Patrick Seale at KI September 2014 (pdf) 

September 2014 - Sven Enerbäck

Visiting researcher: Sven Enerbäck, M.D., Ph.D, Professor in medical genetics at the University of Gothenburg.
Title of seminar: Brown fat - of mice and men.

Poster: seminar by Sven Enerbäck at KI September 2014 (pdf)

November 2013 - Elsa Rodrigues

Visiting researcher: Elsa Rodrigues, Ph.D. Faculty of Pharmacy, University of Lisbon. Molecular and Cell Biology of Eukaryotic Systems.
Title of seminar: The private life of brain cholesterol.

November 2013 - Maria Joao Gama

Visiting researcher: Maria Joao Gama, Ph.D. Faculty of Pharmacy, University of Lisbon. Molecular and Cell Biology of Eukaryotic Systems. 
Title of seminar: Transcriptional responses to oxidative stress: Role of KEAP1-NRF2-ARE pathway.

November 2013 - Leslie Leinwand

Visiting researcher: Leslie Leinwand, Ph.D. University of Colorado at Boulder. BioFrontiers Institute. 
Title of seminar: Translating python biology to the mammalian heart.

Poster: seminar by Leslie Leinwand at KI November 2013 (pdf) 

October 2013 - Anthony Rosenzweig

Visiting researcher: Anthony Rosenzweig, M.D., Director of Cardiovascular Research and Associate Chief of Cardiology at the Beth Israel Deaconess Medical Center (BIDMC).
Title of seminar: Novel insights into cardioprotection and repair from models of exercise.

Poster: seminar by A Rosenzweig at KI October 2013 (pdf)

November 2012 - Evan Rosen

Visiting researcher: Evan Rosen, M.D., Ph.D. Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA. 
Title of seminarAn epigenomic basis for metabolic dysfunction: changes taken out of sequence.

Poster: seminar by Evan Rosen at KI November 2012 (pdf)

September 2012 - Nika Danial

Visiting researcher: Nika Danial, Ph.D, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA. 
Title of seminar: Apoptosis meets metabolism - A role for the Bcl-2 family protein BAD in nutrient sensing.

Poster: seminar by Nika Danial at KI september 2012 (pdf) 

Contact us

Associate professor

Jorge Ruas

Phone: 08-524 872 61
Organizational unit: Ruas Jorge group - Molecular and Cellular Exercise Physiology
E-mail: Jorge.Ruas@ki.se

 

Physiology